Faculty Bibliography

Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema.

BACKGROUND/AIMS/OBJECTIVE:To describe the clinical outcomes of patients with circumscribed and diffuse choroidal hemangiomas treated by proton beam irradiation using a nonsurgical light-field technique. METHODS:A retrospective chart review was performed on a series of 19 patients (19 eyes) with choroidal hemangiomas treated with proton beam therapy between July 1988 and August 2005. Choroidal hemangiomas were treated with proton beam irradiation using a light-field technique and doses ranging from 15 to 30 cobalt Gray equivalents (CGE; CGE = proton Gy x relative biological effectiveness 1.1) in 4 fractions. Patients with at least 6 months' follow-up were included in the study. Tumor regression, visual acuity, absorption of subretinal fluid, and treatment-associated complications were evaluated by clinical examination and ultrasonography. RESULTS:Visual acuity improved or remained stable in 14 of 18 eyes (78%). Subretinal fluid was initially present in 16 of 19 eyes (84%), and completely resolved in all 16 eyes. Tumor height, as measured by B-scan ultrasonography, decreased in 18 of 19 eyes and remained stable in 1 of 19, as of the last examination. Complications of radiation developed in 9 of 19 eyes (47%) with the total applied dose ranging from 15 to 30 CGE for these 9 eyes. CONCLUSIONS:Proton beam irradiation using a light-field technique without surgical tumor localization is an effective treatment option in managing both circumscribed choroidal hemangiomas and diffuse hemangiomas associated with Sturge-Weber syndrome. A total proton dose as low as 15 CGE applied in 4 fractions appears to be sufficient to reduce tumor size, promote absorption of subretinal fluid, and improve or stabilize vision in most patients.

PURPOSE/OBJECTIVE:To investigate the agreement between confocal scanning laser tomography and quantitative fluorescein angiography in the analysis of retinal-thickness changes in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). MATERIALS AND METHODS/METHODS:The edema index of a cSLT was measured in 18 eyes of 16 patients with CNV secondary to AMD that underwent photodynamic therapy (PDT) with Visudyne. Measurements were taken 1 hour before as well as 1 hour, 1 month, and 3 months after therapy. Moreover, a custom-written algorithm was used to analyze the integrated contrast amplitude (ICA) of fluorescein angiograms acquired before as well as 1 month and 3 months after PDT. Confocal scanning laser analysis of the edema index (EI) before and after PDT and correlation of the results with quantitative fluorescein angiography was performed. RESULTS:A statistical significant increase of the EI was observed 1 hour after PDT. Nonetheless, no other statistical significant change over time was observed either on the EI or the ICA. Significant correlation was observed between the EI and the ICA as well as their changes over time, yet better results were observed when non-parametric correlation was calculated. CONCLUSIONS:The axial intensity profile of the cSLT and the edema index provide important information with respect to the neovascular membranes and correlate well with quantitative fluorescein angiography. The application of cSLT and the EI provide an important tool that could complement the investigation of new treatments of neovascular membranes.

PURPOSE/OBJECTIVE:Azurocidin, released by neutrophils during leukocyte-endothelial interaction, is a main cause of neutrophil-evoked vascular leakage. Its role in the retina, however, is unknown. METHODS:Brown Norway rats received intravitreal injections of azurocidin and vehicle control. Blood-retinal barrier (BRB) breakdown was quantified using the Evans blue (EB) dye technique 1, 3, and 24 hours after intravitreal injection. To block azurocidin, aprotinin was injected intravenously before the intravitreal injections. To investigate whether azurocidin plays a role in vascular endothelial growth factor (VEGF)-induced BRB breakdown, rats were treated intravenously with aprotinin, followed by intravitreal injection of VEGF(164). BRB breakdown was quantified 24 hours later. To investigate whether azurocidin may mediate BRB breakdown in early diabetes, aprotinin or vehicle was injected intravenously each day for 2 weeks to streptozotocin-induced diabetic rats, and BRB breakdown was quantified. RESULTS:Intravitreal injection of azurocidin (20 microg) induced a 6.8-fold increase in vascular permeability compared with control at 1-3 hours (P < 0.05), a 2.7-fold increase at 3 to 5 hours (P < 0.01), and a 1.7-fold increase at 24 hours (P < 0.05). Aprotinin inhibited azurocidin-induced BRB breakdown by more than 95% (P < 0.05). Furthermore, treatment with aprotinin significantly suppressed VEGF-induced BRB breakdown by 93% (P < 0.05) and BRB breakdown in early experimental diabetes by 40.6% (P < 0.05). CONCLUSIONS:Azurocidin increases retinal vascular permeability and is effectively blocked by aprotinin. The inhibition of VEGF-induced and early diabetic BRB breakdown with aprotinin indicates that azurocidin may be an important mediator of leukocyte-dependent BRB breakdown secondary to VEGF. Azurocidin may become a new therapeutic target in the treatment of retinal vascular leakage, such as during diabetic retinopathy.

PURPOSE/OBJECTIVE:To evaluate the treatment parameters necessary for achieving ciliary body photodynamic damage, enough to significantly reduce IOP, using verteporfin and a diode laser. DESIGN/METHODS:Animal study. METHODS:The right eye ciliary body of 30 pigmented rabbits was irradiated using verteporfin (Visudyne) and a diode laser. Photosensitizer dose ranged from 0.375 to 2 mg/kg. Three adjacent laser spots were applied 0.5 mm behind limbus at 12 o'clock position using a contact transscleral technique. The laser power was ranging from 10 to 70 mW and the duration of irradiation from 1 to 5 min per spot. The left eyes of the rabbits were used as controls. Animals were sacrificed 24 hours after the procedure and their eyes were evaluated by means of light and electron microscopy. A step-by-step approach was adopted with adjustment of experimental parameters according to histological findings. The end point was to identify the irradiation parameters necessary for induction of photodynamic damage while minimizing thermal damage. Subsequently, 10 more animals were used in order to verify the effectiveness of these irradiation parameters in reducing the intraocular pressure. RESULTS:The therapy parameters that led to photodynamic effect avoiding thermal damage were laser power of 25 mW, irradiation time of 3 min per spot, and verteporfin dose of 1 mg/kg. Transscleral ciliary body irradiation using these parameters resulted in vascular thrombosis of ciliary vessels and in substantial edema, resulting in separation of the two ciliary epithelium layers. These parameters were applied to 4 rabbits, resulting in a mean IOP reduction of 1.8 mmHg +/- 1.2 that lasted for 4 days. An increase of the laser power to 35 mW tested in 6 additional animals, resulted in mean IOP reduction of 2.2 mmHg +/- 1.2, lasting 6 days; some minimal thermal damage was seen with the later settings. CONCLUSION/CONCLUSIONS:The combination of verteporfin and 690 nm diode laser is effective for the induction of ciliary body photodynamic damage, which results in significant but temporary IOP reduction, after transscleral PDT in pigmented rabbits. With appropriate parameter selection, intraocular pressure reduction can be achieved while thermal damage is kept to a minimum.

PURPOSE/OBJECTIVE:Photoreceptor apoptosis is associated with retinal detachment (RD) induced photoreceptor degeneration. Previously, we demonstrated the importance of caspase activation for RD-induced photoreceptor death in a rat model of RD. However, extracellular signals that precede the activation of caspases and photoreceptor degeneration remain unclear. The aim of this study is to characterize the molecular and cellular responses that occur after RD. The expression of cytokines, chemokines, and growth factors were examined in a rat model of RD. METHODS:RD was induced in adult rats by subretinal injection of sodium hyaluronate. Retinal tissues were collected at various times (1, 3, 6, 24, and 72 h) after the induction of detachment. To screen for expressional changes in response to RD, major candidates for cytokines, chemokines, and growth factors were broadly examined by quantitative real time polymerase chain reaction (QPCR). To identify the cellular sources of the expressed genes, cells from various layers of the retina were obtained using laser capture microdissection (LCM), and their mRNAs were isolated. Protein expression was quantified by immunohistochemistry and Enzyme Linked-Immuno-Sorbent Assay (ELISA). To assess the potential of early response genes after RD to induce photoreceptor degeneration, exogenous recombinant proteins were subretinally injected and the photoreceptor cell death was assessed using a TdT-dUTP terminal nick-end labeling (TUNEL) assay at 24 h after RD. RESULTS:At 72 h after RD a significant increase in mRNA levels for tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), monocyte chemotactic protein-1 (MCP-1), and basic fibroblast growth factor (bFGF) were detected in the neural retina. LCM revealed increased expression of mRNA for bFGF and MCP-1 in all retinal layers, though bFGF was especially evident in the outer nuclear layer (ONL) and MCP-1 in the inner nuclear layer (INL). TNF-alpha was increased in the ONL and the INL, and IL-1beta was increased in the ganglion cell layer. Time course experiments showed that TNF-alpha, IL-1beta and MCP-1 increased within 1 h after RD, while bFGF was increased by 24 h. Increased protein expression for TNF-alpha, IL-1beta, and MCP-1 was demonstrated by ELISA at 6 h after RD. Immunohistochemistry showed TNF-alpha and bFGF expression in the whole retina, with IL-1beta specifically expressed in astrocytes and MCP-1 in Müller cells. Subretinal administration of MCP-1 significantly increased TUNEL-positive cells in the ONL 24 h after RD, while injection of vehicle control, TNF-alpha, or IL-1beta showed no effect. CONCLUSIONS:Retinal glial cells, including astrocytes and Müller cells, are a major source of cytokine induction after RD. The increased expression and release of MCP-1 may be an important cause of photoreceptor degeneration associated with RD. This study helps to understand the mechanisms of RD-induced photoreceptor degeneration. Our results may provide new therapeutic targets to prevent photoreceptor degeneration following RD.

PURPOSE/OBJECTIVE:To assess the repeatability of macula measurements provided by the Heidelberg Retina Tomograph II (HRT II) in normal subjects, patients with diabetic macular edema (DME), and patients with choroidal neovascularization (CNV). DESIGN/METHODS:Prospective, observational case. SETTING/METHODS:Institutional-based study. PATIENT POPULATION/METHODS:Ten normal eyes, 14 eyes with DME, and 14 eyes with CNV. OBSERVATIONAL PROCEDURE/METHODS:Three scans within a single day. An additional three scans of each of the 10 normal eyes on a different day. MAIN OUTCOME MEASURES/METHODS:Bland and Altman analysis for a 0.25 mm, 0.50 mm, and 0.75 mm radius circle. RESULTS:Variability and repeatability of the measurements were not related to circle size for either group of patients. Coefficient of variability values of the normal group and a 0.50-mm radius circle were 17%, 5.7%, and 6.1% for mean surface height, signal width, and edema index, respectively. The corresponding values were 15.6%, 10%, and 10% for the DME group, and 10.5%, 7.4%, and 8.5% for the CNV group. The 95% confidence interval of the difference between single observations across days of the normal group was +/-106 microm, +/-80 microm, and +/-0.10 for mean surface height, signal width, and edema index, respectively. When three scans were combined, the corresponding values were +/-61.5 microm, +/-46.7 microm, and +/-0.06. CONCLUSIONS:The repeatability and variability of measurements of normal subjects, patients with DME, and patients with CNV were determined. Differences between the three groups exist and are important for diagnosing a pathologic condition or measuring the effect of various treatments.